The mBio Diagnostics division of Precision Photonics Corporation (mBio/PPC) is developing a low-cost, point-of-care (POC), combination Treponemal/Nontreponemal Syphilis diagnostic device. The Syphilis test will be built on the mBio SnapEsiTM multiplexed serology system, which performs serological disease diagnosis by simultaneously measuring antibodies against multiple antigens. Syphilis remains a major public health concern. It is a sexually transmitted and congenital disease caused by the bacterium Treponema pallidum. When properly diagnosed, it is readily treatable with relatively inexpensive antimicrobial therapies. Around the globe, annual syphilis infection statistics are grim, with 12 million people infected. Congenital syphilis kills more than one million infants per year. Syphilis infection is particularly grave in the context of HIV infection, as genital ulcers in active syphilis increase the risk of HIV transmission. At the same time, syphilis disease progression is greatly accelerated in immunocompromised individuals. Most current syphilis testing is based on decades-old, laboratory-based, nontreponemal tests (RPR &VDRL) utilized with confirmatory testing in multi-test algorithms. Treponemal rapid tests have been introduced in global markets and offer the advantage of a point-of-care result. The rapid tests, however, do not deliver the active disease quantitative titer information provided by the nontreponemal tests. Improved point-of-care syphilis testing will lead to better individual patient outcomes, reduced disease spread, and will potentially reduce overall healthcare system costs. Here we propose development of simple, low-cost, combination Treponemal / Nontreponemal point-of-care syphilis diagnostic system called the SnapEsiTM Syphilis T/NT. mBio/PPC currently has a preliminary Treponemal serology assay working on its SnapEsi POC diagnostic system. SnapEsi is a minimally instrumented, cartridge-based device for assays based on panels of biomarkers. Phase I of the proposed research will focus on development of a quantitative nontreponemal assay and selection of the final set of Treponemal antigens. Working with infectious disease clinicians at the University of California, San Diego, 100 clinical samples will be sourced and characterized as part of Phase I, providing the basis for preliminary sensitivity and specificity calculations. Phase I positions the technology for a larger test development and epidemiology effort in Phase II. Phase II will focus on clinical testing, testing economics, and disease epidemiology in the context of HIV co-infection. The proposed system fills an important unmet need for improved POC syphilis testing, while at the same time establishing a platform for eventual multi-pathogen test rollout. The long term vision is a syphilis rapid test with parallel HIV testing in the same test cartridge. Such a system presents an opportunity for enormous cost savings in limited resource settings, where a multiplicity of manual, single-pathogen rapid tests will become costly and unwieldy.